CCL20 produced in the cytokine network of rheumatoid arthritis recruits CCR6+ mononuclear cells and enhances the production of IL-6

Although a notable amount of CCL20 is detectable in the synovial fluid of human rheumatoid arthritis (RA), its role in the pathogenesis of RA remains to be determined. IL-1β vigorously induced the production of CCL20 from FLSs of human RA and the production of CCL20 induced by TNF-α was partially attributed to a trace amount of IL-1β induced by TNF-α. Although IL-6 failed to induce CCL20, TNF-α-induced IL-6 enhanced the production of CCL20 in an autocrine/paracrine manner. To determine the role of CCL20 and its sole receptor CCR6 in the recruitment of mononuclear cells (MNCs) into the inflamed joint of RA, conditioned medium of IL-1β-stimulated FLSs was used in migration assays. The conditioned medium significantly recruited CCR6+ MNCs in a CCL20-dependent manner. The production of CCL20 induced by TNF-α and IL-1β was modified by helper-T-cell-derived cytokines. Interestingly, CCL20 enhanced the production of IL-6 coordinately with the stimulation of IL-17 but not with that of IFN-γ. These findings imply FLSs stimulated by proinflammatory cytokines recruit CCR6+ MNCs including IL-17-producing-helper T cells into the inflamed joint, leading to the enhancement of the production of CCL20, which chemokine and IL-17 coordinately induce proinflammatory cytokines.